ETS factors promote oncogenic transformation in the context of Pten loss by altering AR output.
Major finding: ETS factors promote oncogenic transformation in the context of Pten loss by altering AR output.
Mechanism: ERG and ETV1 function as pioneer factors to enhance AR binding and transcriptional activity.
Impact: A new conditional mouse model provides a useful tool to study ETS-driven prostate tumorigenesis.
Oncogenic rearrangements involving ETS family genes frequently occur in prostate cancer and result in tissue-specific expression of ETS transcription factors including ERG and ETS variant gene 1 (ETV1). However, existing transgenic ETS mouse models have shown only a minimal tumor phenotype, and the mechanisms underlying ETS-driven prostate tumorigenesis remain poorly understood. To address these issues, Chen and colleagues generated a conditional mouse model in which the TMPRSS2–ERG fusion was uniformly expressed specifically in prostate epithelial cells. Consistent with previous reports, ERG expression alone was not sufficient to initiate prostate tumors, but cooperated with genetic deletion of Pten to induce highly penetrant prostatic intraepithelial neoplasia and progression to invasive adenocarcinoma. Intriguingly, genome-wide androgen receptor (AR) binding was increased in ERG-expressing mice compared with wild-type mice; a large percentage of new AR peaks mapped to genes containing ERG binding sites within preexisting enhancer regions marked by histone 3 lysine 4 methylation, suggesting that ERG may function as a pioneer factor to promote AR recruitment and transcriptional activity. ERG triggered robust transcriptome changes in the context of Pten deficiency similar to ERG-mediated changes in human prostate cancer, including regulation of genes that modulate cell death, inflammation, migration, and angiogenesis, and stimulated AR transcriptional activity in the absence of Pten. Furthermore, ETS factors also positively regulated AR binding and transcriptional output in ETV1-translocated, PTEN-deficient human prostate cancer cells, supporting the notion that ETS-dependent modulation of AR binding primes the prostate epithelium to respond to upstream signals and restores AR function following PTEN loss. These findings establish this mouse model as a useful tool for additional mechanistic studies and suggest that ETS factors induce prostate-specific transformation via regulation of the AR cistrome.